Many types of eukaryotic cells have the ability to sense gradients of chemoattractants and to migrate toward the sources of these attractants, and this kind of chemical-gradient-guided cell migration is called chemotaxis. Chemotaxis is essential for development and immunity in mammals, and it also plays a key role in pathological events such as cancer metastasis and inflammation. The knowledge on cellular functions of chemotaxis has been enriched by the ability of monitoring dynamic behaviors of cells in diverse tissues and revealing chemoattractant gradients in these environments. The understanding of the molecular mechanisms has largely benefited from studies to identify components and mechanisms involved in chemotaxis. However, it is still not clear how these components work together to detect a gradient and to achieve directional cell migration. Here, we highlight recent progress in GPCR-mediated chemotaxis at the cellular and molecular levels.